The vast majority of strokes in post-menopausal women, as in men, are the result of ischemic cerebral injury caused by atherosclerotic disease (thrombus and embolus formation). Numerous studies have shown that men who have had a stroke almost always have an atherosclerotic lesion at the bifurcation of the common carotid artery. Although far fewer studies have been conducted among women, and almost all have involved small sample sizes, the data implicate high-grade stenotic lesions at the carotid bifurcation as the most likely cause of stroke.^3,4

Atherosclerotic lesions at the carotid bifurcation frequently are calcified and have been shown to be detectable on the panoramic dental radiographs of neurologically asymptomatic high-risk male veterans.^5,6 A review of the literature, however, reveals only two studies in which female participants (as well as male participants) were assessed for atheroma formation on panoramic radiographs.^7,8 The mean ages (40 and 32 years) of the populations studied,^7,8 however, were quite young, and so these subjects were at low risk of experiencing atheroma formation. The prevalence rate of atheroma formation among the women in these studies was 2 percent, but their atherogenic risk factors (that is, obesity, smoking, hypertension, hyperlipidemia, diabetes mellitus) could not be determined because their data were combined with the data for men with atheromas. Information regarding menopause status, hormone replacement therapy, or HRT, if any and laboratory test results were not reported.

Therefore, we undertook this research project to determine the prevalence of atheromas on the panoramic radiographs of an exclusively postmenopausal female population aged 55 years and older and to identify all of their atherogenic risk factors.

Atherosclerotic lesions at the carotid bifurcation frequently are calcified and have been detected on the panoramic dental radiographs of neurologically asymptomatic high-risk male veterans.

	MATERIALS AND METHODS

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The study population of 52 subjects was recruited from 567 consecutively screened patients treated at the Women’s Health Clinic, Veterans Affairs Outpatient Clinic, Sepulveda, Calif. Inclusion criteria were female sex, age 55 years or older, a history of amenorrhea of at least 12 months’ duration and a standard panoramic radiograph of diagnostic quality. Exclusion criteria were a history of a transient ischemic attack or a history of a cerebrovascular accident.

Equipment. A research dental assistant obtained radiographs of the subjects using a panoramic X-ray system operated at 10 milliamperes and 75 kilovolts and dental film. The exposed radiographs were developed with an automatic developer.

Methods. One of us (A.F.) examined the radiographs in subdued ambient light using transmitted light from a standard viewing box and a rheostat-controlled 75-watt bulb (a "hot" light) for the presence of calcified carotid artery atheromas. Subjects whose panoramic radiograph exhibited a calcification in the area of the carotid bifurcation then underwent radiographic examination of the anteroposterior view of the cervical spine for confirmation of the presence of an atheroma. Criteria for the differential diagnosis of atheromas on panoramic and cervical spine radiographs have been published elsewhere.^6,9

We reviewed the medical records of the study population for risk factors known to be associated with atherosclerosis in women. Specifically assessed were demographic characteristics, hypertension, excess weight/obesity, age at natural or surgically induced menopause, type of oral HRT (that is, estrogen alone or estrogen combined with progestin), lipid profile, diabetes mellitus and smoking habits.

Patients reported physician-diagnosed hypertension or current use of antihypertensive medication. Being "overweight" was defined as having a body mass index, or BMI (calculated as kilograms/meter²), of 27 to 29.9, and "obesity" was defined as a BMI of 30 or higher.¹⁰ Fasting plasma lipid analyses included measurement of total cholesterol levels (normal reference range, 146 to 200 milligrams/deciliter) and low-density lipoprotein, or LDL, cholesterol levels (normal reference range, 62 to 130 mg/dL), calculated according to the Friedewald equation.¹¹

We determined that subjects had diabetes if they reported having received a diagnosis from their physician, currently used insulin or oral hypoglycemic medication, or had a fasting plasma glucose level greater than 126 mg/dL on two separate occasions.¹² A positive smoking history was defined as having smoked more than 15 pack-years during a lifetime (that is, the equivalent of one pack of cigarettes smoked per day for 15 years).

We analyzed the data by compiling the demographic information and calculating the prevalence rates of calcified carotid artery atheromas and atherosclerosis-associated risk factors for the study population and for the subgroups with and without atheroma formation. In addition, we compared the prevalence rates of atheroma formation between women who had been postmenopausal for 10 or more years and had received HRT for more than 50 percent of that time and women who had been postmenopausal for 10 or more years and had never received HRT. We used the Fisher exact test (categorical variables) or Student t test (continuous variables) to conduct statistical comparisons between subgroups with and without atheroma.

	RESULTS

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The study population consisted of 49 white women and three African-American women (n = 52), with a mean age of 70.4 years and an age range of 55 to 90 years. A review of their medical histories revealed that 36 (69 percent) of the subjects were hypertensive, eight (15 percent) had a BMI of 27 to 29.9 and 15 (29 percent) had a BMI of 30 or greater. The majority (75 percent) of subjects had gone through natural (physiological) menopause at a mean age of 49.3 years, and 25 percent had gone through surgical (artificial) menopause after a hysterectomy (surgical removal of the uterus and cervix) and an accompanying oophorectomy (surgical removal of both ovaries) at a mean age of 38.2 years.

Hormone replacement therapy. At the time that subjects underwent radiography, they had been postmenopausal for a mean of 24 years (range, six to 43 years). Thirty-seven (71 percent) of the women were receiving HRT, with 22 (42 percent) receiving estrogen alone for a mean of 8.5 years (range, one to 38 years) and 15 (29 percent) receiving estrogen and progestin for a mean of 5.8 years (range, six months to 20 years). One subject had received a course of estrogen alone for two years, followed by a six-year course of estrogen and progestin.

Risk factors. Atherogenic risk factors were common, with 32 subjects (62 percent) having an elevated total serum cholesterol level (mean level, 238 mg/dL), 23 (42 percent) having an elevated LDL cholesterol level (mean level, 154 mg/dL) and 11 (19 percent) having type 2 diabetes mellitus. Smoking also was common, with 15 (29 percent) of the 52 subjects reporting having smoked during their lives. These subjects had smoked a mean of 37.5 pack-years, with a range of 15 to 65 years.

Panoramic radiographs. The panoramic radiographs of 16 white subjects (31 percent), with a mean age of 72.1 years (range, 56 to 84 years), exhibited calcified carotid artery disease. Eight subjects had unilateral opacities and eight had bilateral opacities (Figures 1 and 2). Anteroposterior cervical spine radiographs confirmed that each of these 16 women had calcified carotid artery atheromas; however, for two of the eight subjects whose panoramic radiographs showed unilateral atheromas, bilateral atheromas were found on the anteroposterior film.

View larger version (92K): [in this window] [in a new window]   Figure 1. Standard panoramic dental radiograph with calcified carotid arterial plaques visible in the right and left sides of the neck (arrows).

View larger version (103K): [in this window] [in a new window]   Figure 2. Cropped panoramic dental radiograph with two calcified carotid arterial plaques visible just anterior to the cervical spine in the left side of the neck (arrows).

Twelve (75 percent) of the 16 women were receiving HRT, with eight (50 percent) receiving estrogen alone (mean duration, 5.4 years [range, two to 15 years]) and three (19 percent) receiving estrogen and progestin (mean duration, four years [range, two to six years]). One subject (6 percent) received estrogen alone for two years, followed by a six-year course of estrogen and progestin.

Atherogenic risk factors were common among the 16 women with atheromas: nine subjects (56 percent) had an elevated total serum cholesterol level (mean level, 245 mg/dL), eight (50 percent) had an elevated LDL cholesterol level (mean level, 151 mg/dL) and three (19 percent) had type 2 diabetes mellitus. Smoking also was common, with six subjects (38 percent) reporting that they had smoked during their lives. These subjects had smoked a mean of 27 pack-years, with a range of 15 to 65 years.

Statistical analysis. Our analysis of discrete risk factors for atherosclerosis performed between the groups of women with and without atheroma formation demonstrated that hypertension was a significant risk factor for the development of arterial disease. However, we found that "ever use" of HRT was unrelated to the presence or absence of atheromas in this study sample.

Thirteen (25 percent) of the 52 subjects in the study reported that they had received long-term HRT (mean time, 14.3 years; mean number of postmenopausal years, 20.5). Panoramic radiography showed that two (15 percent) of these women had atheromas. In contrast, 15 women reported that they had never received HRT (mean number of postmenopausal years, 14). Panoramic radiography showed that three (21 percent) of these women had atheromas. Thus, the difference in prevalence rates between the two groups of subjects was not statistically significant.

We calculated a combined score for risk factors by totaling the number of risk factors that were positive for each subject: hypertension, being overweight (or obese), elevated cholesterol (or LDL) level, diabetes mellitus and smoking (scores ranged from 0 to 5). As shown in the table, the mean number of positive risk factors (2.6, standard deviation = 1.5) for women with atheroma formation was not different from that for women without atheromas (2.1, standard deviation = 1.1).

	DISCUSSION

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The carotid artery calcifications were located within the soft tissues of the neck, approximately 2 centimeters inferior and posterior to the angle of the mandible at about the level of the lower margin of the third cervical vertebra (where discernible). Their distinctive appearance (single or multiple punctuate or verticolinear calcifications) and location readily distinguished them from other confounding opacities (that is, hyoid bone, salivary calculi, phleboliths, calcified lymph nodes, tip of the epiglottis, styloid process and associated ligaments).

The results of our study are consistent with those of a recent high-resolution ultrasonographic study of 2,588 postmenopausal women, which demonstrated that 49 percent of subjects had carotid artery plaques.¹³ Our results are somewhat more modest because panoramic radiographs can detect only those lesions that have significant deposits of calcium, while ultrasonography can detect early lesions that are devoid of calcium or that have minimal amounts of calcium.¹⁴

The women in our study were about 70 years of age, and other studies^15,16 have noted that the age range of 66 to 70 years is the crucial period for women to develop significant atherosclerotic lesions (that is, stenosis of 40 percent or greater) at the carotid bifurcation. Stenotic lesions of this magnitude are capable of reducing cerebral blood flow and are associated with a yearly risk of cerebral infarction of approximately 5 percent.¹⁷ The authors of these studies^13–17 noted, as did we, that hypertension, a disorder common in women at the age of menopause, was a significant risk factor for the development of atherosclerosis in the area of the carotid bifurcation.

Hypertension disrupts the integrity of the carotid vessel’s endothelial lining and initiates plaque formation. Serum lipoproteins and platelet-derived growth factor, or PDGF, pass through the damaged and hyperpermeable endothelium. The lipoproteins lodge in the intima and the PDGFs cause proliferation of smooth muscle cells. The thickened and elevated lesion calcifies primarily at the junction of the intima and media, and protrudes into the vessel lumen, altering the flow of blood.¹⁸

Postmenopausal women also are at high risk of developing carotid artery atherosclerosis because they frequently develop an atherogenic blood lipid profile at the time menses cease. Reduced levels of circulating estrogen are associated with an increase in hepatic lipase activity and a decrease in LDL catabolism, which result in increased levels of LDL cholesterol and reduced levels of HDL cholesterol.^19–21 Reduced levels of circulating estrogen also have been shown in animal models to be associated with enhanced myointimal hyperplasia.^22–24 Although many studies have demonstrated the efficacy of HRT to delay the onset or halt the progression of carotid artery atherosclerosis, our study did not, but this might be the result of having had a small sample size.^25–29

Identifying a calcified carotid artery atheroma on a panoramic radiograph is of major clinical significance. In 1994, Friedlander and colleagues³⁰ observed that the panoramic radiographs of patients who had suffered an ischemic stroke were 10 times more likely to exhibit a calcified carotid artery atheroma than were radiographs of similarly aged, neurologically asymptomatic people. In 1996, in response to the observations of Fried-lander and Friedlander,³¹ Crouse³² noted that atheromas detected on panoramic radiographs were likely to be indicative of generalized atherosclerosis and that patients with such lesions required an intensive medical evaluation of their carotid and coronary arteries. Woodworth and colleagues³³ found that the presence of atheromas on the panoramic radiographs of high-risk patients is a significant predictor of death from cardiovascular disease.

	CONCLUSION

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The results of this study show that some older women with calcified carotid artery atheromas can be identified in the dental office via panoramic radiography. Patients with such calcifications may be at risk of experiencing stroke and should be referred to an appropriate physician for confirmation of the findings and determination of the extent of disease. The control of risk factors, administration of medications and prophylactic surgical removal of the plaque, in selected patients, are safe and reliable methods of reducing the incidence of cerebrovascular accidents.

View larger version (136K): [in this window] [in a new window]   Dr. Friedlander is the associate chief of staff and the director, Graduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System; director, Quality Assurance, Hospital Dental Service, Medical Center at the University of California Los Angeles; and a professor, Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".